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Macrovascular Residual Risk Studies

18 May 2015
Meta-regression analysis nails HDL-C
A meta-regression analysis including more than 160,000 secondary prevention patients in 51 trials reaffirms that high-density lipoprotein cholesterol (HDL-C) is not a target for lipid-lowering therapy. In their conclusion, the authors question the rationale of developing HDL-targeted therapy.
Hourcade-Potelleret F, Laporte S, Lehnert V et al.
Clinical benefit from pharmacological elevation of high-density lipoprotein cholesterol: meta-regression analysis.
Heart 2015;0:1–7. doi:10.1136/heartjnl-2014-306691
Objective: To investigate the relationship between pharmacological change in HDL-C and the effect on coronary heart disease (CHD) using a meta-regression model. This model was then applied to cholesteryl ester transfer protein (CETP) inhibition in the secondary prevention population.
Study design: Meta-regression analysis to explore the relationship between change of HDL-C, low-density lipoprotein cholesterol (LDL-C), total cholesterol and triglycerides (TG) concentrations and coronary risk in randomised controlled trials
Study population: The analysis included 167,311 patients in 51 studies; 31 trials tested statins (n=94,196), 6 trials tested fibrates (n=8,629 patients), 8 trials tested niacin (n=30,124 patients), and 6 tested CETP inhibitors on top of statins (n=34,362 patients). Patients included in this analysis were aged between 47 and 75 years, with the majority males. The average baseline HDL-C value ranged between 31 and 53 mg/dL (0.80-1.37 mmol/L).
Primary efficacity outcome: Coronary events, a composite of non-fatal myocardial infarction and coronary death
Methods: Inverse variance weighted meta-regression analysis was used to explore the relationship between control-corrected change of HDL-C, LDL-C, total cholesterol and TG concentrations and the relative risk of the primary clinical endpoint. Summary estimates of relative risk (RR) were obtained with a fixed-effect model. The fitting model was developed with trials of statins, fibrates and niacin interventions and was used as a basis to predict the effect of CETP inhibitors on coronary risk.
Main results:
  • The meta regression analysis did not show a significant association between change in HDL-C (treatment vs comparator) and logRR of the clinical endpoint. The change in log RR per mg/dL change in HDL-C was 0.0108 (standard error 0.0117), p=0.362. In contrast, there was a significant association between change in LDL-C and logRR of the primary outcome (p<0.0001).
  • The data for CETP inhibitors were consistent with the lack of association between HDL-C and clinical endpoint (relative risk 1.03; 95% CI 0.99–1.21).
Authors’ conclusion: This meta-regression analysis does not show a positive association between treatment effect on HDL-C increase up to 14 mg/dL (0.36 mmol/L) and reduction of coronary events.


The relevance of HDL-C as a modifiable cardiovascular risk factor – the ‘HDL hypothesis’ has long been a controversial issue.  It is now clear that while low plasma HDL-C concentration is undoubtedly a marker of cardiovascular risk, it is NOT a treatment target, supported by genetic and clinical trial data.1-3 The current study using a meta-regression analysis of clinical trials, a complementary approach to address this question empirically, is consistent with this view.

This conclusion is highly relevant in the context of two ongoing outcomes trials with the CETP inhibitors, anacetrapib and evacetrapib, which both lower plasma LDL-C concentration (by 25-35%) and raise HDL-C, on top of statin treatment.4,5 Given that pharmacological HDL-C raising is not associated with clinical benefit, is it therefore likely that any favourable effects from these trials could be driven by further LDL-C lowering (as these agents are given against a statin background), thus reinforcing the ‘lower is better’ LDL view?

Alternatively, there has been suggestion that HDL functionality may offer further insights into the role of HDL, although at the moment this remains within the research domain. However, there is also controversy with this parameter. In a recent study,6 very high HDL-C plasma levels (mean 86 mg/dL or 2.22 mmol/L) were shown to be associated with reduced cholesterol efflux capacity, a key functionality implicated in the putative antiatherogenic actions of HDL.  Alternatively, the composition of the HDL particle may be relevant. In experimental studies, cholesterol-overloaded HDL particles were shown to exert a negative impact on the antiatherogenic functionality of HDL. Moreover, in clinical studies HDL particle composition was shown to independently associate with progression of carotid atherosclerosis.7 This finding might suggest potential for a novel parameter, the HDL cholesterol/HDL particle ratio (i.e. the combination of the cholesterol content and number of HDL particles) as a determinant of the antiatherogenic function of HDL.

Whether HDL composition, particle number, the combination or HDL functionality is relevant to cardiovascular risk is still highly controversial. On the other hand, there is growing evidence to support triglyceride-rich remnant cholesterol (for which elevated nonfasting triglycerides are a marker) as a cardiovascular risk factor.8,9 Thus, while the jury appears to have spoken for HDL-C – and remains uncertain about HDL functionality -  the case for elevated triglycerides and cardiovascular risk continues to strengthen.


1. Voight BF, Peloso GM, Orho-Melander M et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012;380:572-80.

2. Schwartz GG, Olsson AG, Barter PJ. Dalcetrapib in patients with an acute coronary syndrome. N Engl J Med 2013;368:869-70.

3. Tariq SM, Sidhu MS, Toth PP, Boden WE. HDL hypothesis: where do we stand now? Curr Atheroscler Rep 2014;16:398.

4. Cannon CP, Shah S, Dansky HM et al. Determining the Efficacy and Tolerability Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406–15.

5. Nicholls SJ, Brewer HB, Kastelein JJ, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 2011;306:2099–10

6. Agarwala AP, Rodrigues A, Risman M et al. High-density lipoprotein (HDL) phospholipid content and cholesterol efflux capacity are reduced in patients with very high HDL cholesterol and coronary disease. Arterioscler Thromb Vasc Biol 2015 Apr 2. [Epub ahead of print].

7. Qi Y, Fan J, Liu J et al. Cholesterol-overloaded HDL particles are independently associated with progression of carotid atherosclerosis in a cardiovascular disease-free population: a community-based cohort study. J Am Coll Cardiol 2015;65:355-63.

8. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.

9. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427-36.

Key words HDL cholesterol, cardiovascular marker, functionality, CETP inhibitor